Leptin is a hormone secreted by adipocytes that acts as the major signal in a negative feedback loop controlling bodyweight. Leptin treatment of leptin deficient (ob/ob) mice and humans results in profound weight loss, but more common diet-induced obesity is associated with high plasma leptin levels and resistance to leptin's weight-reducing effects. The molecules and signaling pathways that are responsible for the development of leptin resistance are largely unknown, but such molecules would be attractive targets for obesity therapy. This application describes experiments that will clarify the physiological events that lead to leptin resistance and identify candidates that represent novel cellular regulators of leptin sensitivity. These experiments make use of new approaches and models that overcome one of the key technical challenges that has frustrated efforts to study leptin resistance: the difficulty of accessing leptin's direct target cells, a small subset of neurons dispersed throughout the hypothalamus. Finally, the physiological function of candidate leptin regulators will be explored in rodent models of obesity, using a combination of genetic, anatomical, and pharmacological approaches. Special emphasis will be placed on the use of small molecule drugs, accessed through synthetic chemistry, to rapidly validate candidates in vivo. This research plan will help advance my career goal to lead an interdisplinary research laboratory that applies my background in synthetic chemistry and small molecule discovery to address questions in obesity and metabolic disease. The mentored phase of this research will be conducted in the laboratory of Jeffrey Friedman at Rockefeller University, who has been a leader in field of molecular obesity research. PUBLIC HEALTH RELEVANCE: Obesity is a major public heath problem. This research seeks to understand basic mechanisms that control body weight and identify novel drug targets for obesity therapy.